Non-insulin dependent diabetes mellitus is a common chronic disease that develops in most populations in late middle age. The Pima Indians of Arizona have the highest reported prevalence of this disease in the world and in contrast to many populations the disease often presents at an earlier age. As a result of long-term epidemiological studies in the total population, the familial nature of the disease has been well documented, and segregation analyses suggest the possibility of inheritance by a single additive major gene. This project will search for genetic determinants of NIDDM using the techniques of genetic linkage analyses with genetic markers to identify the chromosomal location of inherited determinants of NIDDM in the Pima Indian population. A number of informative pedigrees have been identified and lymphoblast cell lines from informative members of these pedigrees established. DNA from these lymphoblasts is isolated and polymorphic probes applied to search for evidence of linkage of these markers and NIDDM. Probes with established chromosomal locations are being used to screen the genome to detect genetic linkage with NIDDM as described in Project# Z01 DK 69055-02 (Linkage of Markers on chromosome 7 with NIDDM in Pima Indians). Searches for mutations in mitochondrial DNA and in the IRS-1 gene revealed no variants which in other populations had been associated with diabetes. An allele in the beta3-adrenergic receptor gene is associated with earlier age of onset of diabetes among diabetic subjects, suggesting that this gene may play some role in susceptibility in NIDDM. A refinement of the sib-pair linkage analysis method was developed to incorporate data on age of onset of affected siblings and age at examination of unaffected siblings. Simulation studies indicated that this method improves the power of sib-pair analyses.